Amprenavir

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Abstract
The virological/immunological efficacy of amprenavir-containing combination regimens has been evaluated in a small number of clinical trials in patients with HIV infection. Amprenavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) was more effective than 2 NRTIs (in treatment-naive patients) or amprenavir mono-therapy (in treatment-naive or -experienced patients) in double-blind trials. In the only direct comparison with another protease inhibitor as part of triple therapy, amprenavir was less effective than indinavir in treatment-experienced (protease inhibitor-naive) patients. Amprenavir was as effective as other protease inhibitors when given with abacavir in a small nonblind trial. Amprenavir is generally well tolerated (most events are mild or moderate). GI disturbance and rash are the principal treatment-limiting effects. Preclinical data suggest that amprenavir may have a low potential for metabolic disturbances (e.g. lipodystrophy, fat redistribution); such effects have been infrequent in patients treated to date, but longer term experience is needed. I50V is the major HIV protease substitution associated with amprenavir resistance; this mutation is not seen in isolates from patients receiving other available protease inhibitors. Amprenavir-resistant isolates evaluated to date showed no significant cross-resistance to most other protease inhibitors, although some cross-resistance to ritonavir was noted. Many isolates from patients previously treated with other protease inhibitors are susceptible to amprenavir. Amprenavir offers the convenience of twice-daily administration with no food-timing or fluid restrictions, but this may be offset by the large number and size of the capsules. However, pharmacokinetic data support the use of coadministration of amprenavir and ritonavir at reduced dosages, thereby allowing a reduction in the number of amprenavir capsules. Conclusions: Amprenavir-containing combination regimens have shown virological efficacy, and have generally been well tolerated, in patients with HIV infection (primarily treatment-naive or protease inhibitor-naive). The limited number of studies available and the absence of well controlled comparisons with other triple therapies limits the conclusions that can be drawn at present. The clinical value of amprenavir for patients with isolates which are resistant to other protease inhibitors but sensitive to amprenavir, and in treatment-experienced patients in general, requires further investigation. Further evaluation of the amprenavir/ritonavir combination is awaited with interest. Like other members of its class, amprenavir has a particular profile of tolerability, resistance and administration characteristics which should be carefully considered in relation to the needs of individual patients. Amprenavir is a sulfonamide compound which prevents the formation of infectious HIV-1 virions by inhibiting the viral protease enzyme. It produced 90% inhibition of HIV-1 replication at 0.03 to 0.08 µmol/L in human T cell lines or primary human lymphocytes; 50% inhibition was achieved with amprenavir 0.004 to 0.08 µmol/L. Mean 50%-inhibitory concentration (IC50) against 6 zidovudine-sensitive clinical isolates in peripheral blood lymphocytes was 0.012 µmol/L. Most combinations of amprenavir with other antiretroviral drugs had synergistic activity against HIV-1 in vitro. Amprenavir had no significant cytotoxicity against human T-or B-cell lines or bone marrow progenitor cells invitro. Antiretroviral regimens containing amprenavir have produced a range of beneficial effects on markers of immune activation in patients with HIV infection. In contrast to results for other protease inhibitors, little or no effect on lipid metabolism was reported with amprenavir invitroor in mouse models. The I50V substitution was the most common HIV protease mutation in isolates from previously protease inhibitor-naive patients who failed treatment with amprenavir, lamivudine and zidovudine (5 of 48 isolates, 4 of which showed phenotypic amprenavir resistance). In a trial in which treatment was compromised by baseline resistance to study NRTIs, I50V, I54L/M, V32I + I47V and I84V were the primary amprenavir resistance genotypes for isolates from protease inhibitor-naive patients failing treatment with amprenavir plus NRTIs. Amprenavir-resistant isolates in these 2 studies showed no significant cross-resistance to indinavir, saquinavir or nelfinavir; marked cross-resistance to ritonavir was seen for some isolates with I50V or I84V The I50V mutation has not been seen in isolates from patients receiving other available protease inhibitors. Virological data from several studies suggest that the majority of isolates from patients who have previously received other protease inhibitors are susceptible to amprenavir. I84V and I84V plus L10/I/V/F/R were the most important genotypic predictors of phenotypic amprenavir resistance at baseline for patients receiving rescue therapy with amprenavir, abacavir and efavirenz after failure of previous protease inhibitor regimens. Amprenavir is rapidly absorbed after oral administration, with a time to peak plasma concentration of≈1 to 2 hours. Area under the plasma concentration-time curve was dose-proportional over the range 300 to 1200mg in a multiple-dose study. Amprenavir absorption is reduced by intake with food, although food restrictions are limited to avoidance of high fat meals (see Dosage and Administration). The drug is ≈90% protein bound. Animal data suggest that CNS penetration of amprenavir, like that of other protease inhibitors, is limited by P-glycoprotein-mediated efflux. The plasma elimination half-life is about 7 to 11 hours, the longest for any available protease inhibitor. Amprenavir is metabolised primarily by hepatic cytochrome P450 (CYP) 3A4, with most of an administered dose detected as metabolites in faeces. Amprenavir...

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